NM_001868.4:c.14T>C

Variant names:

• chr7-130380534-T-C
• NM_001868.4:c.14T>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001868.4(CPA1):​c.14T>C​(p.Leu5Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L5L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CPA1 NM_001868.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.81

Genes affected

CPA1 (HGNC:2296): (carboxypeptidase A1) This gene encodes a member of the carboxypeptidase A family of zinc metalloproteases. This enzyme is produced in the pancreas and preferentially cleaves C-terminal branched-chain and aromatic amino acids from dietary proteins. This gene and several family members are present in a gene cluster on chromosome 7. Mutations in this gene may be linked to chronic pancreatitis, while elevated protein levels may be associated with pancreatic cancer. [provided by RefSeq, Jan 2015]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.918

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CPA1	NM_001868.4	c.14T>C	p.Leu5Pro	missense_variant	Exon 1 of 10	ENST00000011292.8	NP_001859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CPA1	ENST00000011292.8	c.14T>C	p.Leu5Pro	missense_variant	Exon 1 of 10	1	NM_001868.4	ENSP00000011292.3
CPA1	ENST00000604896.5	c.14T>C	p.Leu5Pro	missense_variant	Exon 1 of 6	3		ENSP00000475021.2
CPA1	ENST00000481342.5	c.-200+125T>C		intron_variant	Intron 1 of 4	3		ENSP00000420218.1
CPA1	ENST00000491460.5	n.41T>C		non_coding_transcript_exon_variant	Exon 1 of 6	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1163424 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 557362

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary pancreatitis Uncertain:1

Feb 27, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L5P variant (also known as c.14T>C), located in coding exon 1 of the CPA1 gene, results from a T to C substitution at nucleotide position 14. The leucine at codon 5 is replaced by proline, an amino acid with similar properties. This alteration was detected in 1/1112 Han Chinese individuals with idiopathic chronic pancreatitis and 0/1580 controls (Wu H et al. Hum Mutat, 2017 Aug;38:959-963). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Uncertain	0.73	D;T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.45	T;T
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.92	D;D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-4.4	D;.
REVEL	Uncertain	0.42
Sift	Uncertain	0.0050	D;.
Sift4G	Uncertain	0.012	D;T
Polyphen		1.0	D;.
Vest4		0.86
MutPred		0.80		Loss of sheet (P = 0.0054);.;
MVP		0.62
MPC		0.58
ClinPred		0.98	D
GERP RS		5.1
Varity_R		0.84
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-130020375;